Melanoma can metastasize at an early stage, and these metastases are typically resistant to medical treatment. In addition, melanoma is rising in incidence and mortality, greatly increasing the need for methods of prevention and treatment. Evidence suggests that chemokines and their receptors are important regulators of tumor immunity, progression, metastasis, and, angiogenesis in many cancers, including melanoma. The activities of chemokines and their receptors have been shown to be altered by polymorphisms but the impact of these changes on melanoma remains to be elucidated. Preliminary work has identified a polymorphism of a single chemokine receptor that influences the risk of melanoma, but as yet no comprehensive investigations of links between melanoma and chemokine or chemokine receptor polymorphisms have been performed. We propose to detail inherited variations in chemokines and their receptors and determine their associations with melanoma risk, survival, and NRAS and BRAF mutational subtypes in the large international population-based Genes, Environment, and Melanoma (GEM) study. We will also determine whether these relationships are modified by age, ultraviolet exposure, phenotypic traits, and polymorphisms in other genes. Few previous studies have simultaneously addressed the 'immunogenicity'of melanoma along with the oncogenic pathways. The results are likely to improve risk prediction and evidence-based recommendations for environmental protection and enable better outcomes prediction and customization of treatment paradigms for affected patients. PUBLIC HEALTH RELEVANCE: The objective of this competitive renewal is to determine whether inherited variants of chemokines and their receptors, which are key modulators of tumor immunity, are associated with melanoma risk, survival, and tumor mutations in melanoma, with a particular focus on covariates of risk: age and ultraviolet radiation. The work will be done in the context of a large international population-based study of over 3,000 melanoma patients. The results should lead to better risk prediction and more evidence-based recommendations for environmental protection and enable better survival prediction and the identification of patient groups most likely to benefit from targeted therapies for melanoma treatment.